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Prevention And Treatment of Hypertension With Algorithm-based therapy (PATHWAY) number 2: protocol for a randomised crossover trial to determine optimal treatment for drug-resistant hypertension.

ABSTRACT: Resistant hypertension is inadequately controlled blood pressure (BP) despite treatment with at least three BP-lowering drugs. A popular hypothesis is that resistant hypertension is due to excessive Na(+)-retention, and that 'further diuretic therapy' will be superior to alternative add-on drugs.Placebo-controlled, random crossover study of fourth-line treatment when added to standard (A+C+D) triple drug therapy: ACE inhibitor or Angiotensin receptor blocker (A) +Calcium channel blocker (C)+Diuretic (D). Patients (aged 18-79 years) with clinical systolic BP ? 140 mm Hg (135 mm Hg in diabetics) and Home BP Monitoring (HBPM) systolic BP average ? 130 mm Hg on treatment for at least 3 months with maximum tolerated doses of A+C+D are randomised to four consecutive randomly allocated 12-week treatment cycles with an ?-blocker, ?-blocker, spironolactone and placebo. The hierarchical coprimary end point is the difference in HBPM average systolic BP between (in order) spironolactone and placebo, spironolactone and the average of the other two active drugs, spironolactone and each of the other two drugs. A key secondary outcome is to determine whether plasma renin predicts the BP response to the different drugs. A sample size of 346 (allowing 15% dropouts) will confer 90% power to detect a 3 mm Hg HBPM average systolic BP difference between any two drugs. The study can also detect a 6 mm Hg difference in HBPM average systolic BP between each patient's best and second-best drug predicted by tertile of plasma renin.The study was initiated in May 2009 and results are expected in 2015. These will provide RCT evidence to support future guideline recommendations for optimal drug treatment of resistant hypertension.Clinicaltrials.gov NCT02369081, EUDract number: 2008-007149-30.

SUBMITTER: Williams B

PROVIDER: S-EPMC4538257 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Prevention And Treatment of Hypertension With Algorithm-based therapy (PATHWAY) number 2: protocol for a randomised crossover trial to determine optimal treatment for drug-resistant hypertension.

Williams Bryan B MacDonald Thomas M TM Caulfield Mark M Cruickshank J Kennedy JK McInnes Gordon G Sever Peter P Webb David J DJ Salsbury Jackie J Morant Steve S Ford Ian I Brown Morris J MJ

BMJ open 20150807 8

<h4>Introduction</h4>Resistant hypertension is inadequately controlled blood pressure (BP) despite treatment with at least three BP-lowering drugs. A popular hypothesis is that resistant hypertension is due to excessive Na(+)-retention, and that 'further diuretic therapy' will be superior to alternative add-on drugs.<h4>Methods and analysis</h4>Placebo-controlled, random crossover study of fourth-line treatment when added to standard (A+C+D) triple drug therapy: ACE inhibitor or Angiotensin rece ...[more]

PMID: 26253568

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Project description:BackgroundOptimal drug treatment for patients with resistant hypertension is undefined. We aimed to test the hypotheses that resistant hypertension is most often caused by excessive sodium retention, and that spironolactone would therefore be superior to non-diuretic add-on drugs at lowering blood pressure.MethodsIn this double-blind, placebo-controlled, crossover trial, we enrolled patients aged 18-79 years with seated clinic systolic blood pressure 140 mm Hg or greater (or ≥135 mm Hg for patients with diabetes) and home systolic blood pressure (18 readings over 4 days) 130 mm Hg or greater, despite treatment for at least 3 months with maximally tolerated doses of three drugs, from 12 secondary and two primary care sites in the UK. Patients rotated, in a preassigned, randomised order, through 12 weeks of once daily treatment with each of spironolactone (25-50 mg), bisoprolol (5-10 mg), doxazosin modified release (4-8 mg), and placebo, in addition to their baseline blood pressure drugs. Random assignment was done via a central computer system. Investigators and patients were masked to the identity of drugs, and to their sequence allocation. The dose was doubled after 6 weeks of each cycle. The hierarchical primary endpoints were the difference in averaged home systolic blood pressure between spironolactone and placebo, followed (if significant) by the difference in home systolic blood pressure between spironolactone and the average of the other two active drugs, followed by the difference in home systolic blood pressure between spironolactone and each of the other two drugs. Analysis was by intention to treat. The trial is registered with EudraCT number 2008-007149-30, and ClinicalTrials.gov number, NCT02369081.FindingsBetween May 15, 2009, and July 8, 2014, we screened 436 patients, of whom 335 were randomly assigned. After 21 were excluded, 285 patients received spironolactone, 282 doxazosin, 285 bisoprolol, and 274 placebo; 230 patients completed all treatment cycles. The average reduction in home systolic blood pressure by spironolactone was superior to placebo (-8·70 mm Hg [95% CI -9·72 to -7·69]; p<0·0001), superior to the mean of the other two active treatments (doxazosin and bisoprolol; -4·26 [-5·13 to -3·38]; p<0·0001), and superior when compared with the individual treatments; versus doxazosin (-4·03 [-5·04 to -3·02]; p<0·0001) and versus bisoprolol (-4·48 [-5·50 to -3·46]; p<0·0001). Spironolactone was the most effective blood pressure-lowering treatment, throughout the distribution of baseline plasma renin; but its margin of superiority and likelihood of being the best drug for the individual patient were many-fold greater in the lower than higher ends of the distribution. All treatments were well tolerated. In six of the 285 patients who received spironolactone, serum potassium exceeded 6·0 mmol/L on one occasion.InterpretationSpironolactone was the most effective add-on drug for the treatment of resistant hypertension. The superiority of spironolactone supports a primary role of sodium retention in this condition.FundingThe British Heart Foundation and National Institute for Health Research.

Dataset Information

Prevention And Treatment of Hypertension With Algorithm-based therapy (PATHWAY) number 2: protocol for a randomised crossover trial to determine optimal treatment for drug-resistant hypertension.

Publications

Prevention And Treatment of Hypertension With Algorithm-based therapy (PATHWAY) number 2: protocol for a randomised crossover trial to determine optimal treatment for drug-resistant hypertension.

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